Lumican, also known as LUM, is an extracellular matrix protein that, in humans, is encoded by the LUM gene on chromosome 12.
Structure
Lumican is a proteoglycan Class II member of the small leucine-rich proteoglycan (SLRP) family that includes decorin, biglycan, fibromodulin, keratocan, epiphycan, and osteoglycin.
Like the other SLRPs, lumican has a molecular weight of about 40 kiloDaltons and has four major intramolecular domains:
- a signal peptide of 16 amino acid residues;
- a negatively-charged N-terminal domain containing sulfated tyrosine and disulfide bond(s);
- ten tandem leucine-rich repeats allowing lumican to bind to other extracellular components such as collagen;
- a carboxyl terminal domain of 50 amino acid residues containing two conserved cysteines 32 residues apart.
There are four N-linked sites within the leucine-rich repeat domain of the protein core that can be substituted with keratan sulfate. The core protein of lumican (like decorin and fibromodulin) is horseshoe shaped. This enables it bind to collagen molecules within a collagen fibril, thus helping keep adjacent fibrils apart.
Function
Lumican is a major keratan sulfate proteoglycan of the cornea but is ubiquitously distributed in most mesenchymal tissues throughout the body. Lumican is involved in collagen fibril organization and circumferential growth, corneal transparency, and epithelial cell migration and tissue repair. Corneal transparency is possible due to the exact alignment of collagen fibers by lumican (and keratocan) in the intrafibrillar space.
Clinical significance
Mice that have the lumican gene knocked out (Lum-/-) develop opacities of the cornea in both eyes and fragile skin. The lumican (LUM) gene was thought to be a candidate susceptibility gene for high myopia; however, a meta-analysis showed no association between LUM polymorphism and high myopia susceptibility in all genetic models studied.
Lum knockout mice also have abnormal collagen in their heart tissue, with fewer and thicker fibrils. Mice deficient in both lumican and fibromodulin develop severe tendinopathy (tendon pathology), revealing the importance of these SLRPs in the development of correctly sized and aligned collagen fibers in tendon. Along with other extracellular matrix components, lumican expression was increased in equine flexor tendons six weeks after an injury.
Lumican is present in the extracellular matrix of uteral tissues in fertile women. There is an increase of lumican during the proliferative to secretory phase of the endometrium. In menopausal endometrial tissue, the level of lumican expression decreases and is also low in pathological compared to normal endometrium.
Lumican is highly expressed in pleural effusions (lung fluid) of patients with adenocarcinoma. Its expression was low in cancer cells but high in the extracellular matrix surrounding the tumor. Lumican expression was not associated with tumor grade or stage. In about half the patients with pancreatic ductal adenocarcinoma tested, lumican in the extracellular matrix around the tumor was associated with a reduction in metastatic recurrence after surgery and with a three-fold longer survival than patients without stromal lumican. As lumican can directly bind to and inhibit matrix metalloproteinase-14 (MMP14), lumican may limit tumor progression by preventing extracellular matrix collagen proteolysis by this enzyme.
Further reading
- Grover J, Chen XN, Korenberg JR, Roughley PJ (Sep 1995). "The human lumican gene. Organization, chromosomal location, and expression in articular cartilage". The Journal of Biological Chemistry. 270 (37): 21942–9. doi:10.1074/jbc.270.37.21942. PMID 7665616.
- Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- Rada JA, Cornuet PK, Hassell JR (Jun 1993). "Regulation of corneal collagen fibrillogenesis in vitro by corneal proteoglycan (lumican and decorin) core proteins". Experimental Eye Research. 56 (6): 635–48. doi:10.1006/exer.1993.1081. PMID 8595806.
- Hillier LD, Lennon G, Becker M, Bonaldo MF, Chiapelli B, Chissoe S, Dietrich N, DuBuque T, Favello A, Gish W, Hawkins M, Hultman M, Kucaba T, Lacy M, Le M, Le N, Mardis E, Moore B, Morris M, Parsons J, Prange C, Rifkin L, Rohlfing T, Schellenberg K, Bento Soares M, Tan F, Thierry-Meg J, Trevaskis E, Underwood K, Wohldman P, Waterston R, Wilson R, Marra M (Sep 1996). "Generation and analysis of 280,000 human expressed sequence tags". Genome Research. 6 (9): 807–828. doi:10.1101/gr.6.9.807. PMID 8889549.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- Matsushima N, Ohyanagi T, Tanaka T, Kretsinger RH (Feb 2000). "Super-motifs and evolution of tandem leucine-rich repeats within the small proteoglycans--biglycan, decorin, lumican, fibromodulin, PRELP, keratocan, osteoadherin, epiphycan, and osteoglycin". Proteins. 38 (2): 210–25. doi:10.1002/(SICI)1097-0134(20000201)38:2<210::AID-PROT9>3.0.CO;2-1. PMID 10656267. S2CID 39643243.
- Svensson L, Närlid I, Oldberg A (Mar 2000). "Fibromodulin and lumican bind to the same region on collagen type I fibrils". FEBS Letters. 470 (2): 178–82. doi:10.1016/S0014-5793(00)01314-4. PMID 10734230. S2CID 46539089.
- Pellegata NS, Dieguez-Lucena JL, Joensuu T, Lau S, Montgomery KT, Krahe R, Kivelä T, Kucherlapati R, Forsius H, de la Chapelle A (May 2000). "Mutations in KERA, encoding keratocan, cause cornea plana". Nature Genetics. 25 (1): 91–5. doi:10.1038/75664. PMID 10802664. S2CID 8837115.
- Neame PJ, Kay CJ, McQuillan DJ, Beales MP, Hassell JR (May 2000). "Independent modulation of collagen fibrillogenesis by decorin and lumican". Cellular and Molecular Life Sciences. 57 (5): 859–63. doi:10.1007/s000180050048. PMID 10892350. S2CID 21998935.
- Grover J, Liu CY, Kao WW, Roughley PJ (Dec 2000). "Analysis of the human lumican gene promoter". The Journal of Biological Chemistry. 275 (52): 40967–73. doi:10.1074/jbc.M004134200. PMID 11016924.
- Naito Z, Ishiwata T, Kurban G, Teduka K, Kawamoto Y, Kawahara K, Sugisaki Y (May 2002). "Expression and accumulation of lumican protein in uterine cervical cancer cells at the periphery of cancer nests". International Journal of Oncology. 20 (5): 943–8. doi:10.3892/ijo.20.5.943. PMID 11956587.
- Lu YP, Ishiwata T, Kawahara K, Watanabe M, Naito Z, Moriyama Y, Sugisaki Y, Asano G (Aug 2002). "Expression of lumican in human colorectal cancer cells". Pathology International. 52 (8): 519–26. doi:10.1046/j.1440-1827.2002.01384.x. PMID 12366811. S2CID 38324942.
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- Bunkenborg J, Pilch BJ, Podtelejnikov AV, Wiśniewski JR (Feb 2004). "Screening for N-glycosylated proteins by liquid chromatography mass spectrometry". Proteomics. 4 (2): 454–65. doi:10.1002/pmic.200300556. PMID 14760718. S2CID 29261009.
- Botella LM, Sanz-Rodriguez F, Sanchez-Elsner T, Langa C, Ramirez JR, Vary C, Roughley PJ, Bernabeu C (Jan 2004). "Lumican is down-regulated in cells expressing endoglin. Evidence for an inverse correlationship between Endoglin and Lumican expression". Matrix Biology. 22 (7): 561–72. doi:10.1016/j.matbio.2003.11.006. PMID 14996436.
- Vuillermoz B, Khoruzhenko A, D'Onofrio MF, Ramont L, Venteo L, Perreau C, Antonicelli F, Maquart FX, Wegrowski Y (Jun 2004). "The small leucine-rich proteoglycan lumican inhibits melanoma progression". Experimental Cell Research. 296 (2): 294–306. doi:10.1016/j.yexcr.2004.02.005. PMID 15149859.
- Köninger J, Giese T, di Mola FF, Wente MN, Esposito I, Bachem MG, Giese NA, Büchler MW, Friess H (Sep 2004). "Pancreatic tumor cells influence the composition of the extracellular matrix". Biochemical and Biophysical Research Communications. 322 (3): 943–9. doi:10.1016/j.bbrc.2004.08.008. PMID 15336555.
- Li Y, Aoki T, Mori Y, Ahmad M, Miyamori H, Takino T, Sato H (Oct 2004). "Cleavage of lumican by membrane-type matrix metalloproteinase-1 abrogates this proteoglycan-mediated suppression of tumor cell colony formation in soft agar". Cancer Research. 64 (19): 7058–64. doi:10.1158/0008-5472.CAN-04-1038. PMID 15466200.